School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia.
Division of Structural Biology, The Institute of Cancer Research, London SW3 6JB, UK.
Nucleic Acids Res. 2024 May 22;52(9):5285-5300. doi: 10.1093/nar/gkae107.
The signal recognition particle (SRP) is a critical component in protein sorting pathways in all domains of life. Human SRP contains six proteins bound to the 7S RNA and their structures and functions have been mostly elucidated. The SRP68/72 dimer is the largest SRP component and is essential for SRP function. Although the structures of the SRP68/72 RNA binding and dimerization domains have been previously reported, the structure and function of large portions of the SRP68/72 dimer remain unknown. Here, we analyse full-length SRP68/72 using cryo-EM and report that SRP68/72 depend on each other for stability and form an extended dimerization domain. This newly observed dimerization domain is both a protein- and RNA-binding domain. Comparative analysis with current structural models suggests that this dimerization domain undergoes dramatic translocation upon SRP docking onto SRP receptor and eventually comes close to the Alu domain. We propose that the SRP68/72 dimerization domain functions by binding and detaching the Alu domain and SRP9/14 from the ribosomal surface, thus releasing elongation arrest upon docking onto the ER membrane.
信号识别颗粒 (SRP) 是所有生命领域中蛋白质分拣途径的关键组成部分。人源 SRP 包含六个与 7S RNA 结合的蛋白，其结构和功能已基本阐明。SRP68/72 二聚体是 SRP 中最大的组成部分，对于 SRP 功能至关重要。虽然已经报道了 SRP68/72 的 RNA 结合和二聚化结构域的结构，但该二聚体的大部分结构和功能仍不清楚。在这里，我们使用 cryo-EM 分析全长的 SRP68/72，并报告 SRP68/72 彼此依赖以保持稳定，并形成扩展的二聚化结构域。这个新观察到的二聚化结构域既是一个蛋白结合域，也是一个 RNA 结合域。与现有结构模型的比较分析表明，该二聚化结构域在 SRP 与 SRP 受体结合时会发生剧烈的易位，并最终接近 Alu 结构域。我们提出，SRP68/72 二聚化结构域通过结合和分离核糖体表面上的 Alu 结构域和 SRP9/14 来发挥作用，从而在与内质网膜结合时释放延伸阻滞。
